Significant progress was made on this research project during this reporting period. Following our initial breakthrough finding that cannabinoid CB2Rs in the brain modulate cocaine action in mice we used highly selective CB2 agonists and antagonists, combined with the use of CB1-KO and CB2-KO mice and molecular neurobiology electrophysiology techniques to examine the presence, distribution, and function of CB2Rs in the brain. We, for the first time, found that: 1) functional CB2Rs are expressed in VTA DA neurons in mice and rats and activation of CB2R inhibits DA neuron activity and DA release in the nucleus accumbens; 2) different CB2R gene transcripts are found in the brain and periphery in mice (CB2A, CB2B) and in rats (CB2A, CB2B, CB2C, CB2D); 3) there are significant species differences in CB2R structures, cell type-specific expression, and receptor responses to CB2R ligands; 4) CB2R expression in the brain is inducible and dynamic. Chronic cocaine use can up-regulate CB2R expression in VTA DA neurons; and 5) functional CB2Rs are also found in the hippocampus, particularly in CA2 and CA3 pyramidal cells. Moreover, activation of CB2R by endocannabinoids (2-AG) released from local pyramidal neurons self-modulates (inhibits) neuronal activity by activating the sodium-bicarbonate co-transporter. Together, these findings suggest that brain CB2Rs may be new promising targets in medication development for the treatment of addiction and other CNS disorders. Future studies will be focused on CB2R-based medication development by testing various CB2R ligands for the treatment of drug abuse and addiction in preclinical animal models.